Longitudinal analysis of anti-drug antibody development in multiple sclerosis patients treated with interferon beta-1a (Rebif™) using B cell receptor repertoire analysis.

A significant proportion of multiple sclerosis (MS) patients treated with interferon beta-1a (Rebif™) develop anti-drug antibodies (ADA) with a negative impact on treatment efficacy. We hypothesized that high-throughput B-cell receptor (BCR) repertoire analysis could be used to predict and monitor ADA development. To study this we analyzed 228 peripheral blood samples from 68 longitudinally followed patients starting on interferon beta-1a.

Short report: Real-life analysis of the occurrence of persistent, transient, and fluctuating positive titres of neutralizing anti-drug antibodies in multiple sclerosis patients treated with interferon beta.

Interferon beta (IFNβ) is a first line therapy for treatment of multiple sclerosis (MS). However, up to 47% of treated patients will develop neutralizing anti-drug antibodies (NAbs) against IFNβ, which at high titres can inhibit the therapeutic effect of the drug. This study aimed to determine the frequency of transient and fluctuating NAb positivity in a real-world clinical routine setting using a large retrospective international cohort of IFNβ-treated MS patients collected as a part of the ABIRISK consortium (n = 9657).

Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS.

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations.

Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier.

A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab.

Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study.

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera.

Prediction of natalizumab anti-drug antibodies persistency.

Background: Anti-drug antibodies (ADA) against natalizumab develop early during treatment. ADA persistency is defined by two consecutive positive results as performed by the current qualitative ELISA assay (positive/negative). Very little is known about the magnitude of the natalizumab ADA response and persistency.

Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies.

Background: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown.

Objective: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients.

Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta.

Objective: To develop and validate a method for the detection of binding anti-drug antibodies (ADAs) against interferon beta (IFN-β) in human serum as part of a European initiative (ABIRISK) aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization to minimize the risk.

Method: A two-tiered bridging enzyme-linked immunosorbent assay (ELISA) format was selected and validated according to current recommendations. : ADA in serum samples form complexes with immobilized IFN-β and biotinylated IFN-β, which are then detected using HRP labeled Streptavidin and TMB substrate.

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results.

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries.

Development and validation of cell-based luciferase reporter gene assays for measuring neutralizing anti-drug antibodies against interferon beta.

Neutralizing anti-drug antibodies (NAbs) against therapeutic interferon beta (IFNβ) in people with multiple sclerosis (MS) are measured with cell-based bioassays. The aim of this study was to redevelop and validate two luciferase reporter-gene bioassays, LUC and iLite, using a cut-point approach to identify NAb positive samples. Such an approach is favored by the pharmaceutical industry and governmental regulatory agencies as it has a clear statistical basis and overcomes the limitations of the current assays based on the Kawade principle.

Anti-interferon beta antibody titers strongly correlate between two bioassays and in vivo biomarker expression, and indicates that a titer of 150 TRU/mL is a biologically functional cut-point.

Interferon beta (IFNβ) is used as a first-line treatment in relapsing-remitting multiple sclerosis (MS). The occurrence of neutralizing antidrug antibodies (NAbs) against IFNβ may reduce treatment response. Therefore, clinical monitoring of NAbs is currently executed using bioassays, but several bioassays are available and it is unclear how well their readouts correlate.

Smoking and risk of treatment-induced neutralizing antibodies to interferon β-1a.

Background: Neutralizing antibodies (NAbs) to interferon β (IFNβ) products that develop during treatment are associated with a loss of clinical efficacy.

Objectives: The aim of this study was to investigate the influence of smoking habits on the risk of developing NAbs to IFNβ, in the treatment of multiple sclerosis (MS).

Methods: This report is based on 695 MS patients treated with IFNβ-1a, included in two Swedish case-control studies that collected information on smoking habits.